Research ReportThe tuberal lateral hypothalamus is a major target for GABAA- but not GABAB-mediated control of food intake
Introduction
γ-aminobutyric acid (GABA) was identified as a major inhibitory neurotransmitter in the vertebrate brain in 1950 (Awapara et al., 1950, Roberts and Frankel, 1950) and it has since been implicated in the etiology of multiple neurological dysfunctions, including mood disorders, anxiety, epilepsy, insomnia and even addiction (Schousboe and Waagepetersen, 2007). Accumulating evidence suggests that it also plays a role in the control of feeding behavior and body weight regulation, particularly in the hypothalamus. Administration of ionotropic GABAA receptor agonists into hypothalamic areas including the paraventricular nucleus (PVN), ventral medial hypothalamus (VMH), dorsomedial hypothalamus (DMH) and arcuate nucleus (ARC) elicits feeding in satiated rats (Bellinger and Bernardis, 2002, Grandison and Guidotti, 1977, Kelly and Grossman, 1979, Tsujii and Bray, 1991). In contrast, studies have shown that GABAA receptor antagonists acutely injected into the lateral hypothalamus (LH) elicit feeding in satiated rats and we have recently shown that chronic injection leads to reversible body weight loss (Kelly et al., 1977, Turenius et al., 2009). Gene transfer of the enzyme responsible for the production of GABA, glutamic acid decarboxylase (GAD), using an adenoviral vector, has been shown to decrease both food intake and body weight (Noordmans et al., 2004).
Although these findings provide evidence for a behaviorally selective effect of GABA and the GABAA receptors in the control of food intake and body weight regulation, the anatomical specificity of these effects has not adequately been addressed. This is a concern, as centrally injected substances may spread considerable distances from the site of injection (Myers et al., 1971). To address this we performed two cannula mapping studies. In the first, we measured food intake produced by picrotoxin (PIC) injected into five areas bracketing the LH. In the second study, we refined this by testing sites within the LH that are immediately anterior (+ 1.5 mm) and posterior (− 1.5 mm) to the tuberal LH (tLH).
Given the available immunochemical data suggesting that GABAB receptors are present in the LH (Backberg et al., 2003, Margeta-Mitrovic et al., 1999) and that peripheral and intracerebroventricular data suggest that GABAB receptors participate in food intake regulation (Patel and Ebenezer, 2004, Sato et al., 2007) we also tested whether LH GABAB receptors suppressed food intake. Our findings show that the LH, specifically the tLH, is a major site of action for GABAA receptor but not GABAB receptor modulation of feeding behavior.
Section snippets
Experiment 1A. PIC elicits feeding specifically in the LH
Cannula placements in six brain areas are shown in representative sections in Figs. 1A–F.
As shown in Fig. 2D, PIC at 133 pmol elicited a robust feeding stimulatory effect when injected into the LH. In particular, LH rats ate an average of 4.9 g within 30 min post-injection, with little further increase in food intake in subsequent intervals up to 4 h. Two-way ANOVA revealed significant main effects of site (F5, 687 = 43.2, p < 0.001), dose (F3, 687 = 20.1, p < 0.001) and their interaction (F15, 687 =
Discussion
The LH has been implicated in control of feeding, beginning with the seminal findings of Anand and Brobeck (1951) showing that bilateral lesions of the LH resulted in aphagia. Though some doubts were cast by the findings that chemical lesions that damaged passing fibers also produced severe motor impairments along with aphagia (Marshall et al., 1974, Rodgers et al., 1965), the notion that the LH was important in positive energy regulation was later supported by chemical lesions that spared
Subjects and surgery
Adult male Sprague–Dawley rats bred in an on-campus vivarium were used. Under sodium pentobarbital (50 mg/kg i.p.) anesthesia, subjects weighing 350–450 g were stereotaxically implanted with a single 26-gauge stainless steel guide cannula into the LH, entopeduncular nucleus (EPN), dorsomedial hypothalamus (DMH), lateral preoptic area (LPO), ventral tegmental area (VTA), thalamus (THAL), anterior lateral hypothalamus (aLH), tLH or posterior LH (pLH). Target coordinates are given in Table 1.
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Cited by (22)
Distribution of histaminergic neuronal cluster in the rat and mouse hypothalamus
2015, Journal of Chemical NeuroanatomySite selective activation of lateral hypothalamic mGluR1 and R5 receptors elicits feeding in rats
2015, Physiology and BehaviorCitation Excerpt :As previous studies with mGluR5 agonist and antagonists used intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) routes of injection, there is little data to specify the brain sites mediating the elicited feeding [13,18,19]. Mapping studies have shown that the LH is the most effective site for ionotropic glutamate receptor agonist or GABAA receptor antagonists to elicit feeding [5,20–23]. As shown in Fig. 2 of the present study, the LH was the most sensitive site tested for the group I mGluR agonist to induce feeding.
Behaviorally specific versus non-specific suppression of accumbens shell-mediated feeding by ipsilateral versus bilateral inhibition of the lateral hypothalamus
2013, Behavioural Brain ResearchCitation Excerpt :Specifically, activation of N-methyl-d-aspartate receptors (NMDARs) or blockade of GABA subtype A receptors (GABAARs) will induce feeding, and will do so with behavioral specificity [3–5]. Mapping studies show that the LH is a primary site for these effects [6,7]. Also, LH administration of the NMDAR antagonist D-AP5 or the GABAAR agonist muscimol will suppress drug-elicited, nocturnal, and deprivation-induced feeding in rats [4,8].
Evidence that the nucleus accumbens shell, ventral pallidum, and lateral hypothalamus are components of a lateralized feeding circuit
2012, Behavioural Brain ResearchCitation Excerpt :The former possibility is supported by reports that the AcbSh sends a heavy projection to the LH [10,11,15], which presumably contains GABA colocalized with various peptides. Inactivation of the AcbSh would thus be expected to reduce GABA release within the LH, and intra-LH injections of GABA antagonists have been found to induce feeding [32–35], although this result has not always been obtained [14]. The reasons for discrepancies are unclear, and may relate to the exact doses and placements studied or the test diets employed.